The Role of IL-4 in Heligmosomoides polygyrus-Induced Alterations in Murine Intestinal Epithelial Cell Function

Abstract

IL-4 and IL-13 promote gastrointestinal worm expulsion, at least in part, through effects on nonlymphoid cells, such as intestinal epithelial cells. The role of IL-4/IL-13 in the regulation of intestinal epithelial function during Heligmosomoides polygyrus (Hp) infection was investigated in BALB/c mice infected with Hp or treated with a long-lasting formulation of recombinant mouse IL-4/αIL-4 complexes (IL-4C) for 7 days. Separate groups of BALB/c mice were drug-cured of initial infection and later reinfected and treated with anti-IL-4R mAb, an antagonist of IL-4 and IL-13 receptor binding, or with a control mAb. Segments of jejunum were mounted in Ussing chambers, and short circuit current responses to acetylcholine, histamine, serotonin, PGE2, and glucose were determined. Although only modest changes in epithelial cell function were observed during primary Hp infection, IL-4C or a secondary Hp infection each induced more dramatic changes, including increased mucosal permeability, reduced sodium-linked glucose absorption, and increased Cl− secretory response to PGE2. Some, but not all, effects of IL-4C and Hp infection were dependent on enteric nerves. Hp-induced changes in epithelial function were attenuated or prevented by anti-IL-4R mAb. Thus, IL-4/IL-13 mediate many of the effects of Hp infection on intestinal epithelial cell function and do so both through direct effects on epithelial cells and through indirect, enteric nerve-mediated prosecretory effects. These immune system-independent effector functions of IL-4/IL-13 may be important for host protection against gastrointestinal nematodes.

Role of STAT6 and Mast Cells in IL-4- and IL-13-Induced Alterations in Murine Intestinal Epithelial Cell Function

“…These findings expand those of our previous report (11) in two significant ways. First, our observation that IL-4 and IL-13 affect the intestinal epithelial secretory response to 5-HT is novel, in that it was not investigated in mice treated with anti-IL-4R␣ mAb.…”

“…We showed previously that IL-4 mediates a decrease in glucose absorption and an increase in fluid secretion in mice infected with the gastrointestinal nematode parasite H. polygyrus, suggesting that this effect of IL-4 may contribute to IL-4-dependent worm expulsion (11). In this study, we compare the effects of in vivo administration of a long-acting formulation of IL-4 with the effects of in vivo administration of the related cytokine, IL-13, on intestinal epithelial cell function, and determine the contribution of STAT6 signaling to these cytokineinduced alterations in intestinal physiology.…”

“…Gastrointestinal nematode infections, afflicting nearly 1 billion people worldwide (1,2), generally invoke a type 2 cytokine response (3), and are characterized by the production of IL-4, IL-5, IL-6, IL-9, and IL-13 in the infected host (4 -6). Up-regulation of these cytokines results in elevations in serum IgE, eosinophilia, and hyperplasia of mucosal mast cells (MMC) 3 (4) that secrete soluble mediators, including histamine and PGE 2 , which affect epithelial cell function (7)(8)(9)(10)(11).…”

Mast cells disrupt epithelial barrier function during enteric nematode infection

“…However, unlike T. spiralis, expulsion of N. brasiliensis does not depend on mast cells (32), and the cell type or factors that increase enteric leakiness during this infection remained undefined. Shea-Donohue et al (33) stimulated tissue from Heligmosomoides polygyrus-challenged mice with prostaglandin E2 and observed a rise in chloride ion secretion. This response was blocked when mice were treated with anti-IL-4 receptor antibodies.…”

Peripheral CD4 T Cells Rapidly Accumulate at the Host:Parasite Interface during an Inflammatory Th2 Memory Response

“…An inflammatory cell infiltrate develops around the invading parasitic larvae, resulting in a border of cells that delineate a loosely defined, cyst-like structure (5,6). Although the mechanism of worm expulsion remains uncertain, direct effects of IL-4 and IL-13 on gut tissue are probably important (7)(8)(9), and some studies have suggested that an effective memory response is also associated with delayed larval development before emergence into the lumen (5,10). The CD4 T cell response has not been examined at peripheral sites of infection, but pronounced increases in CD4 T cell IL-4 and IL-13, but not IFN-␥, are detected in the mesenteric lymph node (MLN) as early as day 8 after primary inoculation and secondary challenge (11,12).…”